For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.

For the past 70 years, dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling, antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there was limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal, senescence, brain volume loss, attenuation of gamma oscillations on electroencephalogram and oxidation of lipids in plasma and mitochondrial membranes. We surmise that aberrant activation of aryl hydrocarbon receptor by toxins derived from the gut microbes or the environment drives premature cellular, including neuronal, senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: 1. To summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders. 2. To discuss novel strategies for improving long-term outcome in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor.

The COVID-19 pandemic was an eye-opener for many medical disciplines. It highlighted viral exploitation of physiological cellular processes, including endocytosis and cellular senescence. These pathways play an essential role in cancer, neurodegenerative disorders, and schizophrenia (SCZ). Oxytocin, commonly called the “love hormone,” is produced in the posterior hypothalamus and is crucial for various physiological processes, including social intelligence, sexual activity, and metabolism. Many viruses, including SARS-CoV-2, have been shown to inhibit the release of oxytocin from intestinal epithelial cells, thus hastening gut barrier senescence. Premature molecular aging at this level enables microbial migration outside the intestinal lumen, triggering inflammation and immunogenicity. The gut microbial community is immunologically tolerated within the gastrointestinal tract but can activate host immunity upon translocation. Immune responses to displaced commensals and/or their components may contribute to neuroinflammation and gray matter volume reduction, a hallmark of severe mental illness. Oxytocin opposes microbial translocation into the systemic circulation through several mechanisms, including anti-inflammatory, tight junctions-upregulation, and suppression of senescence-associated secretory phenotype—the toxic secretome produced by senescent cells. Limosilactobacillus reuterii, a commensal microbe known for producing oxytocin, shows antiviral and anti-translocation effects, implying a beneficial role in schizophrenia. This condition has been linked to a dysfunctional gut barrier and increased microbial migration outside the intestinal lumen, suggesting that oxytocin replacement therapy could benefit patients with this mental illness. This review article summarizes the current understanding of oxytocin's role in schizophrenia and discusses natural and synthetic compounds that promote gut barrier homeostasis.

Severe mental illnesses, including schizophrenia and schizophrenia-like disorders, have been associated with premature neuronal and glial senescence, microglial activation, and gray matter volume reduction. These changes may drive clinical symptoms of schizophrenia, including cognitive impairment. Aryl hydrocarbon receptor, abundantly expressed in the intestinal and blood–brain barrier, is the master regulator of both tight junctions and cellular senescence. Under pathological circumstances, this receptor may promote premature gut aging, enabling the translocation of bacteria or their components from the gastrointestinal tract into systemic circulation and from there into the central nervous system. In this review article, we discuss a potential mechanism of schizophrenia–microorganismal migration, microglial activation, and gray matter volume reduction. We also focus on potential interventions for maintaining barrier function. These approaches include natural and synthetic modulators of the aryl hydrocarbon receptor as well as biophysical strategies to preserve barrier integrity and prevent central nervous system pathology.

Post-traumatic stress disorder (PTSD) is a severe neuropsychiatric condition characterized by anxiety-related symptoms, including intrusive memories. However, the exact anatomic location of traumatic memories remains unclear. Traumatic imagery may involve the amygdala and posterior cingulate cortex, rather than the hippocampus. Besides the central nervous system, cells and even proteins can process information and store memories. For instance, >36% of cardiac transplant recipients inherit donor personality traits, emphasizing that tissues can store and recall memories. Moreover, physical therapists mention “musculofascial memories,” that is, the ability of muscles and fascia to retain the memory of past injuries and adapt their function accordingly. Immune cells record previous infections, demonstrating the broader perspective of memory storage in the body. At the cellular level, psychological stress induces premature cellular senescence, a survival program characterized by proliferation arrest; resistance to apoptosis; and a toxic secretome known as the senescence-associated secretory phenotype (SASP). SASP contains brain-derived neurotropic factor (BDNF), a neurotrophin linked to fear memory that is frequently elevated in the peripheral blood of patients with PTSD. Endothelial cells (ECs), the tiles paving the lumen of large and small vessels, age earlier than other cells in patients with severe mental illness, including PTSD. Senescent ECs release SASP directly into the systemic circulation, spreading senescence throughout the body. In this narrative review, we hypothesize that ECs store traumatic memories and SASP-associated BDNF activates traumatic imagery. We also discuss membrane lipid replacement, mitochondrial transplantation and transfer, and several natural and synthetic compounds that may counteract endothelial senescence and SASP.

Mycoplasma is the smallest, independently replicating microbe that lacks a cell wall and resembles a liposome because of its sterol-rich cell membrane. Under pathological circumstances, Mycoplasmas cause respiratory and urogenital infections in humans. Human immunodeficiency virus (HIV) is known to be associated with Mycoplasma genitalium, suggesting that viruses may commonly utilize Mycoplasmas to enhance infec-tivity. Along this line, COVID-19 critical illness was documented in individuals with con-comitant Mycoplasma infection, raising the possibility of a symbiotic relationship or binary biological weapon. Binary biological weapons are comprised of two components that are safe to handle separately but, in combination, be-come lethal. For example, concomitant infection with hepatitis D and B is deadly because the D virus takes advantage of the proteins expressed by the B virus, turning hepatitis B into a fatal disease. Mycoplasmas have been known for their neuropsychiatric manifestations, including psychosis, anxiety, depressive dis-orders, cognitive impairment, and schizophrenia. This is relevant as mycoplasmas, like many antipsychotic drugs, enter host cells via clathrin-dependent endocytic pathways, often dormant in endosomes. Moreover, Mycoplasmas express aryl hydrocarbon receptor (AhR), a transcription factor activated by many ligands relevant to neuropsychiatry, including dopamine, serotonin, melatonin, clozapine, carbidopa, tryptophan, and microbial metabolites. Mycoplasma AhR, like its human counterpart, senses environmental stimuli, including viruses, indicating that it may play a role in the Mycoplas-ma/SARS-CoV-2 symbiosis. This perspective article examines Mycoplasma and its relationship with COVID-19, premature cellular senescence, and major depressive disorder. We also discuss neuropathology potentially associated with designer pathogens and some therapeutic strategies.